Aminoquinoline and aminopyridine derivatives and their use as adenosine a3 ligands

ABSTRACT

Compounds of general formula (I), wherein R 4  and R 5  stand for hydrogen atom or form together an 1,3-butadienyl group, optionally substituted by a methylenedioxy group or one or more straight or branched C 1-4  alkyl group, straight or branched C 1-4  alkoxy group, hydroxy group or halogen atom; are strong adenosine A 3  receptor ligands preferably antagonists.

The present invention relates to adenosine A₃ receptor ligands of the general formula (I), within those preferably antagonists, as well as their salts, solvates and isomers, and the pharmaceutical compositions containing them, to the use of the compounds of the general formula (I), as well as their salts, solvates and isomers, to the preparation of the compounds of the general formula (I) and their salts, solvates and isomers, furthermore to the new intermediates of the general formulae (II) (III) and (IV) and to the preparation thereof.

Adenosine is a well-known component of several endogenous molecules (ATP, NAD⁺, nucleic acids). Besides, it plays an important regulatory role in many physiological processes. The effect of adenosine on heart function was discovered already in 1929. (Drury and Szentgyörgyi, J Physiol 68:213, 1929). The identification of an increasing number of physiological functions mediated by adenosine and the discovery of new adenosine receptor subtypes give possibilities for therapeutic application of specific ligands (Poulse, S. A. and Quinn, R. J. Bioorganic and Medicinal Chemistry 6:619, 1998).

To date, the receptors for adenosine have been classified into three main classes: A₁, A₂ and A₃. The A₁ subtype is partly responsible for inhibiting the adenylate cyclase by coupling to G_(i) membrane protein, partly influences other second messenger systems. The A₂ receptor subtype can be subdivided into two further subtypes—A_(2a) and A_(2b)—, which receptors stimulate the adenylate cyclase activity. The sequence of adenosine A₃ receptors have been recently identified from rat testis cDNA library. Later it was proved that it corresponds to a novel, functional adenosine receptor. The activation of the A₃ receptors is connected also with several second-messenger systems: inhibiting of adenylate cyclase, stimulating of phospholipase C and D.

The adenosine receptors are found in several organs and regulate their functions. Both A₁ and A_(2a) receptors play important roles in the central nervous system and cardiovascular system. In the CNS, the adenosine inhibits the release of synaptic transmitters which effect is mediated by A₁ receptors. In the heart, also the A₁ receptors mediate the negative inotropic, chronotropic and dromotropic effects of adenosine. The adenosine A_(2a) receptors located relatively in a higher amount in the striatum, display a functional interaction with dopamine receptors in regulating the synaptic transmission. The A_(2a) adenosine receptors on endothelial and smooth muscle cells are responsible for adenosine-induced vasodilation.

On the basis of mRNA identification, the A_(2b) adenosine receptors are widely distributed in different tissues. They have been identified almost in every cell type, but its expression is the highest in the intestine and the bladder. This subtype probably also has important regulatory function in the regulation of the vascular tone and plays a role in the function of mast cells.

Contrary to A₁ and A_(2a) receptors, where the tissue distribution was detected on the protein level, the presence of A_(2b) and A₃ receptors was detected on the basis of their mRNA level. Expression levels for A₃ adenosine receptors are rather low comparing to other subtypes and highly species dependent. A₃ adenosine receptors are expressed primarily in the central nervous system, testis, immune system and appear to be involved in the modulation of mediator release from mast cells in immediate hypersensitivity reaction.

The A₃ antagonists published so far in the literature belong to the groups of flavonoides, 1,4-dihydropyridine derivatives, triazoloquinazolines, thiazolonaphthyridines and thiazolopyrimidines. The present invention relates to a novel type of effective A₃ antagonists, which have the aminoquinoline structure.

For therapeutic use it is essential to ensure that the molecule does not bind, or bind only in the case of very high concentration to the A₁, A_(2a) and A_(2b) sub-types of the adenosine receptor. Our present invention relates to the compounds of the general formula (I) as well as their salts, solvates and isomers which have great selectivity for the A₃ subtype of the adenosine receptor.

Our aim was to prepare A₃ ligands first of all with quinoline structure, and within those preferably antagonists, which have strong antagonistic effect and show high selectivity for the A₃ receptor, ie. they inhibit the A₃ receptor in much lower concentration than they inhibit the A₁, A_(2a) and A_(2b) receptors. Further aims were to have stability, bioavailability, therapeutic index and toxicity data which make possible to develope the new compounds into drug substances and that due to their favourable enteral absorbtion the compounds can be applied orally.

We have found that the compounds of the general formula (I)—wherein

-   -   R¹ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl         group;     -   R² stands for hydrogen atom or a straight or branched C₁₋₄ alkyl         group;     -   R³ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl         group, or a phenyl group, thienyl group, or furyl group,         optionally substituted by one or more straight or branched C₁₋₄         alkyl group, straight or branched C₁₋₄ alkoxy group, or halogen         atom, or for a 5- or 6 membered heteroaromatic ring—containing         one, two or three nitrogen atoms or one nitrogen atom and one         oxygen atom or one nitrogen atom and one sulphur atom—     -    optionally substituted by one or more straight or branched C₁₋₄         alkyl group, straight or branched C₁₋₄ alkoxy group, or halogen         atom;     -   R⁴ and R⁵ stand for hydrogen atom or form together an         1,3-butadienyl group, optionally substituted by a methylenedioxy         group or one or more straight or branched C₁₋₄ alkyl group,         straight or branched C₁₋₄ alkoxy group, hydroxy group or halogen         atom;     -   R⁶ stands for hydrogen atom or a cyano group, aminocarbonyl         group, C₁₋₄ alkoxycarbonyl group, or carboxy group;     -   R⁷ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl         group, or a phenyl group, benzyl group, thienyl group or furyl         group, optionally substituted by a methylenedioxy group, or one         or more straight or branched C₁₋₄ alkyl group, straight or         branched C₁₋₄ alkoxy group, hydroxy group, trifluoromethyl         group, cyano group or halogen atom, or for a 5 or 6 membered         heteroaromatic ring—containing one, two or three nitrogen atoms         or one nitrogen atom and one oxygen atom or one nitrogen atom         and one sulphur atom—optionally substituted by one or more         straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄         alkoxy group, or halogen atom,     -   X stands for a —CH₂— group, —NH— group, —NR⁸— group, or a         sulphur atom or an oxygen atom or a sulpho group or a sulphoxy         group—wherein R⁸ stands for a straight or branched C₁₋₄ alkyl         group or C₃₋₆ cycloalkyl group—;     -   n stands for zero, 1 or 2—and their salts, solvates, and isomers         and the salts, solvates of the latter, fulfill the above         criteria.

Detailed meanings of the above listed substituents are as follows:

By a straight or branched C₁₋₄ alkyl group we mean methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, secondary-butyl-, tertiary-butoxy-, preferably ethyl- or methyl group.

By a straight or branched C₁₋₄ alkoxy group we mean methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, secondary-butoxy-, tertiary-butoxy-, preferably ethoxy- or methoxy group.

By a C₃₋₆ cycloalkyl group we mean cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexyl group.

By 1,3-butadienyl-group we mean (—CH═CH—CH═CH—)-group, ie. the pyridine ring substituted by R⁴ and R⁵ substituents means a benzopyridine ring or by its trivial name a quinoline ring.

The heteroaromatic ring containing one or two or three nitrogen atoms means pyrrol, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyrimidine, pyridazine, pyrazine and 1,3,4-triazine ring. The ring is optionally substituted by a C₁₋₄ alkyl, or alkoxy group or by a halogen atom.

The heteroaromatic ring containing one nitrogen atom and one oxygen or sulphur atom means oxazole, isoxazole, thiazole, isothiazole ring. The ring is optionally substituted by a C₁₋₄ alkyl, or alkoxy group or by a halogen atom.

Salts of the compounds of the general formula (I) mean salts given with inorganic and organic acids and bases. Preferred salts are those given with pharmaceutically accepted acids as for instance hydrochloric acid, sulphuric acid, ethanesulphonic acid, tartaric acid, succinic acid, fumaric acid, malic acid, citric acid, and bases, as for instance sodium hydroxide, potassium hydroxide, ethanolamine.

Solvates mean solvates given with various solvents, as for instance with water or ethanol.

The compounds of the general formula (I) show geometric and optical isomerism, therefore the invention also relates to mixtures of the geometric isomers, to racemic or optically active geometric isomers, as well as to their salts and solvates.

A favourable group of the compounds of the general formula (I) is formed by the compounds of the general formula (IA), wherein

-   -   R¹ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl         group;     -   R² stands for hydrogen atom or a straight or branched C₁₋₄ alkyl         group;     -   R³ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl         group, or a phenyl group, thienyl group, or furyl group,         optionally substituted by one or more straight or branched C₁₋₄         alkyl group, straight or branched C₁₋₄ alkoxy group, or halogen         atom, or for a 5- or 6 membered heteroaromatic ring—containing         one, two or three nitrogen atoms or one nitrogen atom and one         oxygen atom or one nitrogen atom and one sulphur atom—optionally         substituted by one or more straight or branched C₁₋₄ alkyl         group, straight or branched C₁₋₄ alkoxy group, or halogen atom;     -   R⁹, R¹⁰, R¹¹, and R¹² independently mean hydrogen atom or         straight or branched C₁₋₄ allyl group, or straight or branched         C₁₋₄ alkoxy group, or hydroxy group or halogen atom, or     -   R⁹ and R¹² stand for hydrogen atom and R¹⁰ and R¹¹ form together         a methylenedioxy group;     -   R⁶ stands for hydrogen atom or a cyano group, aminocarbonyl         group, C₁₋₄ alkoxycarbonyl group, or carboxy group;     -   R⁷ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl         group, or a phenyl group, benzyl group, thienyl group or furyl         group, optionally substituted by a methylenedioxy group, or one         or more straight or branched C₁₋₄ alkyl group, straight or         branched C₁₋₄ alkoxy group, hydroxy group, trifluoromethyl         group, cyano group or halogen atom, or for a 5 or 6 membered         heteroaromatic ring—containing one, two or three nitrogen atoms         or one nitrogen atom and one oxygen atom or one nitrogen atom         and one sulphur atom—optionally substituted by one or more         straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄         alkoxy group, or halogen atom,     -   X stands for a —CH₂— group, —NH— group, —NR⁸— group, or a         sulphur atom or an oxygen atom or a sulpho group or a sulphoxy         group—wherein R⁸ stands for a straight or branched C₁₋₄ alkyl         group or C₃₋₆ cycloalkyl group—;     -   n stands for zero, 1 or 2—     -    and their salts, solvates, optically active isomers and the         salts, solvates thereof.

A favourable group of the compounds of the general formula (IA) is formed by the compounds wherein

-   -   R¹ stands for hydrogen atom, or methyl group;     -   R² stands for hydrogen atom, or methyl group;

R³ stands for phenyl- or thienyl- or furyl group;

-   -   R⁹, R¹⁰, R¹¹, and R¹² mean independently hydrogen atom or         straight or branched C₁₋₄ alkyl group, or straight or branched         C₁₋₄ alkoxy group, or hydroxy group or halogen atom, or     -   R⁹ and R¹² stand for hydrogen atom and R¹⁰ and R¹¹ form together         a methylenedioxy group;     -   R⁶ stands for hydrogen atom, or cyano group;     -   R⁷ stands for 4-methoxyphenyl-, 3-methylphenyl-,         3-methoxyphenyl-, 3-thienyl-, or 3-furyl-group,     -   X stands for —NH— group or for oxygen atom and     -   n stands for 1—     -    and their salts, solvates, optically active isomers and the         salts, solvates thereof

Especially favourable are the following compounds complying with the above criteria:

-   -   3-methyl-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide;     -   4-methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide;     -   3-methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide;     -   3,4-methylenedioxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide;     -   N-(4-benzylamino-3-cyanoquinolin-2-yl)thiophene-2-carboxamide;     -   N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)thiophene-3-carboxamide;     -   4-methoxy-N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)benzamide;     -   3,4-methylenedioxy-N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)-benzamide;     -   N-(4-[2-furylmethylamino]-3-cyanoquinolin-2-yl)furan-2-carboxamide;     -   N-(4-[2-furylmethylamino]-3-cyanoquinolin-2-yl)thiophene-3-carboxamide,     -    and their salts, solvates, optically active isomers and the         salts, solvates thereof.

According to another of its aspects, the present invention also relates to pharmaceutical compositions containing as active principles the compounds of the general formula (I) or their isomers, salts and solvates, which are preferably oral compositions, but inhalable, parenteral and transdermal formulations are also subjects of the invention. The above pharmaceutical compositions may be solids or liquides, such as tablets, pellets, capsules, patches, solutions, suspensions or emulsions. The solid compositions, first of all tablets and capsules are the preferred pharmaceutical forms.

The above pharmaceutical compositions are prepared by applying usual pharmaceutical excipients and by using standard methods.

The compounds of the general formula (I) can be used in treating pathologies, in the development of which A₃ receptor plays a role.

The compounds of the present invention having selective activity on the A₃ receptor can be used in the therapeutic and/or preventive treatment of disfunctions of the heart, kidney, respiratory system, central nervous system. They inhibit the protective effect of adenosine in growing tumor cells, prevent mast cell degranulation, inhibit the cytokine production, reduce the intraocular pressure, inhibit the TNFα release, inhibit the migration of eosinophils, neutrophils and other immune cells, inhibit the bronchoconstriction and plasma extravasation.

Based on these effects, adenosine A₃ receptor antagonists of the present invention may be therapeutically useful as antiinflammatory, antiasthmatic, antiischemic, antidepressant, antiarrhytmic, renal protective, antitumor, antiparkinson and cognitive enhancing drugs. They also may be useful in the treatment or prevention of miocardial reperfusion injury, chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome (ARDS) including chronic bronchitis, pulmonary emphysema or dyspnea, allergic reactions (e.g. rhinitis, poison ivy induced responses, urticaria, scleroderma, arthritis) other autoimmune diseases, inflammatory bowel disease, Addison's disease, Crohn's disease, psoriasis, rheumatism, hypertension, neurogical function disorders, glaucoma and diabetes (K. N. Klotz, Naunyn-Schmiedberg's Arch. Pharmacol. 362:382,2000; P. G. Baraldi és P. A. Borea, TiPS 21:456, 2000).

The compounds of the present invention may be preferable used for the treatment of diseases such as asthma, COPD and ARDS, glaucoma, tumor, allergic and inflammatory diseases, ischemia, hypoxia, arrythmia and renal diseases.

According to another of its aspects, the present invention relates to the use of the compounds of the general formula (I) in the treatment of the above pathologies. Suggested daily dose is 1-100 mg active ingredient depending on the nature and severeness of the disease and on sex, weight etc. of the patient.

Further subject of the invention is the preparation of the compounds of the general formula (I) and of the intermediates of the general formulae (II) (III) and (IV).

The intermediates of the general formulae (II) (III) and (IV) which are used in the preparation process according to the invention, are partly novel. Substituents of the general formulae (II), (III) and (IV) have the meanings as defined above.

In the process according to our invention the bis-carboxamide of the general formula (II) is selectively hydrolysed and the resulting compound of the general formula (I) is, if desired, transformed into its salts, solvates or, liberated from its salt, solvate and separated into its geometric or optical isomers.

Substituents of the compounds of the general formula (I) may be transformed into each other by known methods.

Selective hydrolysis is performed by using alcoholic, preferably methanolic alkali hydroxide solution, preferably potassium and/or sodium hydroxide solutions, but other agents helping the hydrolysis of amides can also be used.

The selective hydrolysis can be carried out in a wide temperature range, favourably between 20° C.-100° C.

The compounds of the general formula (II)—wherein the meanings of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X and n are as defined above—can be obtained by several known methods, among them the one demonstrated in Scheme 1 (FIG. 6), by acylation of the compounds of the formula (III), by using an acylation method known in the organic chemistry. For acylating agent preferably acyl chloride, for acid binding agent triethylamine and/or pyiridine can be applied, but other acid binding agents can also be used.

The compounds of the general formula (III)—wherein the meanings of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, X and n are as defined above—can be prepared from the compounds of the formula (IV)—by using methods known per se (Nan Zhang, Bioorg. and Med. Chem. Lett., 10,2825, 2000).

The compounds of the general formula (IV)—wherein the meanings of R⁴, R⁵ and R⁶ are as defined above—can be prepared from the compounds of the formula (V), by using methods known per se (D. L. Leysen, J. Heterocyclic Chem., 24, 1611, 1987).

The compounds of the general formula (V)—wherein the meanings of R⁴, R⁵ and R⁶ are as defined above—can be prepared from the compounds of the formula (VI), by using methods known per se (Pfizer (Inc) U.S. Pat. No. 4,175,193).

The compounds of the invention, of the general formulae (I), (II), (III) and (IV), their preparation and biological activity are demonstrated in the following Examples, without limiting the scope of claims to the Examples.

FIG. 1 shows general formula (I),

FIG. 2 shows general formula (IA),

FIG. 3 shows general formula (II),

FIG. 4 shows general formula (III) and

FIG. 5 shows general formula (IV).

FIG. 6 shows Scheme 1 the reaction route for the preparation of compounds of the general formula (I).

EXAMPLES Example 1 3-Methyl-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide

In general formula (I) R¹ and R² stand for hydrogen atoms, R³ for phenyl group, R⁴ and R⁵ form together a 1,3-butadienyl group, R⁶ stands for cyano group, R⁷ for 3-methylphenyl group, the meaning of X is —NH group, n is 1.

a.) 2-Amino-3-cyano-4-chloroquinoline

The mixture of 10 g of 2-amino-3-cyano-4-hydroxyquinoline and 15 ml of phosphoryl chloride is heated under stirring at 110 ° C. The reaction mixture is cooled down, poured onto 100 ml of ice-water and neutralized with 60 ml of 10% sodium hydroxide solution. The resulting yellow precipitate is filtered off, washed with 50 ml of water. After drying 7.5 g of the title compound is obtained, mp.: 210° C.

NMR, δ_(H)(400 MHz, DMSO-d₆): 7.21 ppm, (s, 2H, NH₂), 7.35-7.40 ppm, (dd, 1H, 6-H), 7.53-7.57 ppm, (d, 1H, 5-H), 7.70-7.75 ppm, (dd, 1H, 7-H), 7.93-7.98 ppm, (d, 1H, 8-H)

b.) 2-Amino-3-cyano-4-benzylaminoquinoline

5 g of 2-amino-3-cyano4-chloroquinoline and 11 ml of benzylamine are heated under stirring at 130° C. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale-yellow precipitate is recrystallized from dimethylformamide to obtain 5.2 g of the title compound.

Mp.: 206° C.

NMR, δ_(H)(400 MHz, DMSO-d₆): 5.02-5.03 ppm, (d, 2H, N—CH₂), 6.22 ppm, (s, 2H, NH₂), 7.14-7.16 ppm, (dd, 1H, 6-H), 7.24-7.26 ppm, (dd, 1H, 5-H), 7.30 ppm, (s, 5H, Ph), 7.50-7.52 ppm, (dd, 1H, 7-H), 8.16-8.19 ppm, (d, 1H, 8-H), 8.30-8.33 ppm, (t, 1H, NH)

Using 2-aminomethylpyridine or 3-aminomethylpyridine or 4-aminomethylpyridine instead of benzylamine, the appropriate compounds of general formula III can be obtained.

c.) 3-Methyl-N-(3-methylbenzoyl)-N-(4-benzylamino-3-cyanoquinoline-2-yl)benzamide

To the solution of 5 g of 2-amino-3-cyano-4-benzylaminoquinoline in 30 ml of pyridine 6 ml of 3-methylbenzoyl chloride are dropped, under stirring at 0° C. The reaction mixture is stirred at 80° C. for 8 hour, then it is poured onto 150 ml of ice-water. The precipitate is filtered off, washed twice with 40 ml of water. The resulting white crystalline material is recrystallized from 200 ml of ethanol to give 9.2 g of the title compound, mp.: 234° C.

By using pyridine-3-carbonyl chloride as acylating agent, the appropriate compound of general formula II can be obtained.

d.) 3-Methyl-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide

To the solution of 5 g of 3-methyl-N-(3-methylbenzoyl)-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide in 80 ml of acetonitrile 20 ml of 1N methanolic potassium hydroxide solution are added. The reaction mixture is refluxed for 3 minutes, then 3 ml of glacial acetic acid is added to it, then it is neutralized with 50 ml of 1M sodium hydrogen carbonate solution and the resulting crystals are filtered off. The white crystalline material is recrystallized from 130 ml of acetonitrile to give 3.1 g of the title compound of general formula (I). Mp.: 230° C.

Example 2 4-Methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide

In the general formula (I) the meaning of R¹ and R² is hydrogen atom, R³ is phenyl group, R⁴ and R⁵ mean together a 1,3-butadienyl group, R⁶ means cyano group, R⁷ means 4-methoxyphenyl group, X means —NH— group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline, prepared as described in Example 1, is transformed with 4-methoxybenzoyl chloride, analogously as described in Example 1, into 4-methoxy-N-(4-methoxybenzoyl)-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide, which after selective hydrolysis, by the method described in Example 1, results the title compound of general formula (I). Melting point of the title compound: 188° C.

Sodium salt of the title compound is prepared by the following method:

4-methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide is dissolved in methanol and equivalent amount of sodium hydroxide in methanol is added to it. The precipitated white crystalline material is filtered off. Mp.: 255° C.

Ethanesulfonate salt of the title compound is prepared by the following method: 4-methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide is dissolved in methanol and equivalent amount of ethanesulfonic acid is added to it. The precipitated white crystalline material is filtered off. Mp.: 223° C.

Example 3 3-Methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide

In the general formula (I) the meaning of R¹ and R² is hydrogen atom, R³ is phenyl group, R⁴ and R⁵ mean together a 1,3-butadienyl group, R⁶ means cyano group, R⁷ means 3-methoxyphenyl group, X means —NH— group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline, prepared as described in Example 1, is transformed with 3-methoxybenzoyl chloride, analogously as described in Example 1, into 3-methoxy-N-(3 -methoxybenzoyl)-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide, which after selective hydrolysis by the method described in Example 1, results the title compound of general formula (I). Melting point of the title compound: 186° C.

Example 4 3,4-Methylenedioxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide

In the general formula (I) the meaning of R¹ and R² is hydrogen atom, R³ is phenyl group, R⁴ and R⁵ mean together a 1,3-butadienyl group, R⁶ means cyano group, R7 means 3,4-methylenedioxyphenyl group, X means —NH— group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline prepared as described in Example 1, is transformed with 4-methoxybenzoyl chloride analogously as described in Example 1, into 3,4-methylenedioxy-N-(3,4-methylenedioxybenzoyl)-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide which after selective hydrolysis by the method described in Example 1, results the title compound of general formula (I).

Melting point of the title compound: 231° C.

Example 5 N-(4-benzylamino-3-cyanoquinolin-2-yl)thiophene-2-carboxamide

In the general formula (I) the meaning of R¹ and R² is hydrogen atom, R³ is phenyl group, R⁴ and R⁵ mean together a 1,3-butadienyl group, R⁶ means cyano group, R⁷ means 2-thienyl group, X means —NH— group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline prepared as described in Example 1. is transformed with thiophene-2-carbonyl chloride, analogously as described in Example 1, into N-(2-thiophenecarbonyl)-N-(4-benzylamino-3-cyanoquinolin-2-yl)thiophene-2-carboxamide, which after selective hydrolysis, by the method described in Example 1, results the title compound of general formula (I).

Melting point of the title compound: 197° C.

Example 6 N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)thiophene-3-carboxamide

In the general formula (I) the meaning of R¹ and R² is hydrogen atom, R³ is 2-thienyl group, R⁴ and R⁵ mean together a 1,3-butadienyl group, R⁶ means cyano group, R⁷ means 3-thienyl group, X means —NH— group, n is 1.

a) 2-amino-3-cyano4-(2-thienylmethylamino)quinoline

5 g of 2-amino-3-cyano4-chloroquinoline, prepared as described in Example 1, is stirred with 11 ml of 2-thienylmethylamine at 130° C. for 3 hours. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale yellow material is recrystallized from 25 ml of ethanol to obtain 5.2 g of title compound, mp.: 208° C.

The 2-amino-3-cyano-4-(2-thienylmethylamino)quinoline prepared as described above is transformed with thiophene-3-carbonyl chloride, analogously as described in Example 1, into N-(3-thiophenecarbonyl)-N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)-thiophene-3-carboxamide which after selective hydrolysis, by the method described in Example 1, gives the title compound of general formula (I). Melting point of the title compound: 223° C.

Example 7 4-methoxy-N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)benzamide

In the general formula (I) the meaning of R¹ and R² is hydrogen atom, R³ is 2-thienyl group, R⁴ and R⁵ mean together a 1,3-butadienyl group, R⁶ means cyano group, R⁷ means 4-methoxyphenyl group, X means —NH— group, n is 1.

The 2-amino-3-cyano-4-(2-thienylmethylamino)quinoline prepared as described in Example 6. is transformed with 4-methoxybenzoyl chloride into 4-methoxy-N-(4-methoxybenzoyl)-N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)benzamide by the method described in Example 1, which after selective hydrolysis gives the title compound of general formula (I). Melting point of the title compound: 173° C.

Example 8 3,4-methylenedioxy-N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)-benzamide

In the general formula (I) the meaning of R¹ and R² is hydrogen atom, R³ is 2-thienyl group, R⁴ and R⁵ mean together a 1,3-butadienyl group, R⁶ means cyano group, R⁷ means 3,4-methylenedioxyphenyl group, X means —NH— group, n is 1.

2-amino-3-cyano-4-(2-thienylmethylamino)quinoline prepared as described in Example 6. is transformed with 3,4-methylenedioxybenzoyl chloride into 3,4-methylenedioxy-N-(3,4-methylenedioxybenzoyl)-N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)benzamide by the method described in Example 1, which after selective hydrolysis gives the title compound of general formula (I). Melting point of the title compound: 241° C.

Example 9 N-(4-[2-furylmethylamino]-3-cyanoquinolin-2-yl)furan-2-carboxamide

In the general formula (I) the meaning of R¹ and R² is hydrogen atom, R³ is 2-furyl group, R⁴ and R⁵ mean together a 1,3-butadienyl group, R⁶ means cyano group, R⁷ means 2-furyl group, X means —NH— group, n is 1.

a.) 2-Amino-3-cyano4-(2-furylmethylamino)quinoline

5 g of 2-amino-3-cyano-4-chloroquinoline, prepared as described in Example 1 are stirred with 1 ml of 2-furylmethylamine (furfurylamine) at 130° C. for 3 hours. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale yellow material is recrystallized from 20 ml of ethanol to obtain 4.8 g of the title compound, mp.: 208° C.

The 2-amino-3-cyano-4-(2-furylmethylamino)quinoline prepared as described above is transformed with furan-2-carbonyl chloride by the method described in Example 1. into N-(2-furancarbonyl)-N-(4-[2-furylmethylamino]-3-cyanoquinolin-2-yl) furan-2-carboxamide which after selective hydrolysis gives the title compound of general formula (I). Melting point of the title compound: 196° C.

Example 10 N-(4-[2-furylmethylamino]-3-cyanoquinolin-2yl)thiophene-3-carboxamide

In the general formula (I) the meaning of R¹ and R² is hydrogen atom, R³ is 2-furyl group, R⁴ and R⁵ mean together a 1,3-butadienyl group, R⁶ means cyano group, R⁷ means 3-thienyl group, X means —NH— group, n is 1. 1.

The 2-amino-3-cyano4-(2-furylmethylamino)quinoline prepared analogously as described in Example 6. is transformed with thiophene-3-carbonyl chloride by the method described in Example 1. into N-(3-thiophene carbonyl)-N-(4-[2-furylmethylamino]-3-cyanoquinolin-2-yl)thiophene-3-carboxamide which after selective hydrolysis, performed analogously as described in Example 1. gives the title compound of general formula (I). Melting point of the title compound: 118° C.

Structure and physical characteristics of further compounds of general formula (I) prepared by the method described in Example 1. are shown in Tables I. and II.

TABLE I

Mp No.: X R³ R⁶ R⁷ n [° C.] 11. NH

CN

1 237 12. NH

CN

1 128 13. NH

CN

1 116 14. NH

CN

1 100,5 15. NH

CN

1 223 16. NH

CN

1 193,5 17. NH

CN

1 193 18. NH

CN

1 208 19. NH

CN

1 215 20. NH

CN

1 250 21. NH

CN

1 205 22. NH

CN

1 238 23. NH

CN

1 212 24. NH

CN

1 215 25. NH

CN

1 234 26. NH

CN

1 160,5 27. NH

CN —Me 1 184 28. NH

CN

1 141,5 29. NH

CN

1 194 30. NH

CN

1 203 31. NH

CN

1 152 32. NH

CN

1 190 33. NH

CN

1 202 34. NH

CN

1 207 35. NH

CN

1 159 36. NH

CN

1 200 37. NH

CN

1 206 38. NH

CN

1 221 39. NH

CN

1 198 40 NH

CN

1 158 41. NH

CN

1 178 42. NH

CN

1 198,5 43. NH

CN

1 197,5 44. NH

CN

1 191 45. NH

CN

1 168,5 46. N-Me

CN

1 155 47. NH

H

1 172 48. NH

H

1 250 49. NH

H

1 264 50. NH

H

1 265 51. NH

H

1 163 52. O

CN

1 157 53. S

CN

1 196 54. S═O

CN

1 205 55. NH H CN

0 266 56. NH

CN

1 154 57 NH

CN

1 145

TABLE II

Mp R¹ R² R³ R⁴ R⁵ R⁷ [° C.] 58. Me H

165 59. H Me

145 60. H H

119 61. H H

119 62. H H

243 63. H H

176 64. H H

171 65. H H

199 66. H H

203 67. H H

180 68. H H

117 70. H H

153 71. H H

215 72. H H

237 73. H H

275 74. H H

245 75. H H

247 76. H H

222 77. H H

218 78. H H

214 79. H H

252 80. H H

178 81. H H

173 82. H H

212 83. H H

184 84. H H

150 85. H H

195 86. H H

171 87. H H

217 88. H H

149 89. H H

135 90. H H

127 91. H H

257 92. H H

260 93. H H

153 94. H H

145 95. H H

214 96. H H

183 97. H H

H H

167 98. H H

H H

162 99. H H

H H

183 100 H H

H H

216 101 H H

H H

206

Structure and physical characteristics of intermediates of general formula (II) prepared by the method described in Example 1. are shown in Table III.

TABLE III

Mp No.: X R³ R⁶ R⁷ [° C.] 102 NH

CN

213 103. NH

CN

208 104 NH

CN

178s 105 NH

CN

158 106 NH

CN

210 107 NH

CN

223 108 NH

CN

224 109 NH

CN

212 110 NH

CN

198 111 NH

CN

208 112 NH

CN

168 113 NH

CN

168 114 NH

CN

225 115 NH

CN Me 152 116 NH

CN Et 192 117 NH

CN

177 118 NH

CN

169 119 NH

CN

151 120 NH

CN

218 121 NH

CN

194 122 NH

CN

188 123 NH

CN

179 124 NH

CN

239 125 NH

H

162 126 NH

H

262 127 S

CN

170 128

CN

228

Structure and physical characteristics of intermediates of general formula (III) and (IIIa) prepared by the method described in Example 1. are shown in Table IV.

TABLE IV

Mp No.: R¹ R² R³ R⁴ R⁵ X n [° C.] 129 H H

NH 1 192 130 H H

NH 1 202 131 H H

NH 1 250 132 H H

NH 1 167 133 H

NH 1 183 134 H

NH 1 182 135 H H

NH 2 172 136 H H

NH 2 143 137 H

NH 2 129 138 H

NH 2 136 139 H H

N—Me 1 212 140 H H

S 1 168 141 H H

O 1 213 142 H H

NH 1 234 143 H H

NH 1 221 144 H H

NH 1 198 145 H H

NH 1 201 146 H H

NH 1 213 147 H H

NH 1 198 147 H H

NH 1 201 148 H H

NH 1 167 149 H H

NH 1 156 150 H H

NH 1 187 151 H H

NH 1 178 152 H H

NH 1 207 153 H H

NH 1 217 154 H H

NH 1 204 155 H H

NH 1 216 156 H H

NH 1 205 158 H H

NH 1 213 159 H H

NH 1 200 160

NH 0 214

Structure and physical characteristics of intermediates of general formula (V) prepared by the method described in Example 1. are shown in Table V.

TABLE V

No: R⁴ R⁵ Mp [° C.] 161.

360 162.

250 163.

278 164

283 165.

360 166.

234 167

246 168

267 169

293 170

289 171

307

Example 172

Tablets of the following composition are made by known methods used in the pharmaceutical industry

Active ingredient 25 mg Lactose 50 mg Avicel 21 mg Crospovidone  3 mg Magnesium stearate  1 mg

Biology

Methods

Human Adenosine A₃ Receptor Binding

Preparing membrane suspension: collect CHO cells expressing hA₃ receptors by washing three times with ice cold PBS, centrifugate at 1000×g 10 min, homogenize for 15 sec in buffer (50 mM Tris, 10 mM MgCl₂, 1 mM EDTA, pH 8.0), centrifugate at 43,000×g for 10 min (Sigma 3K30), suspense the membrane preparation in the buffer mentioned above, store the aliquots at −80 C. Binding protocol: incubate CHO-hA₃ membrane preparation (2 μg protein content) in incubation buffer (50 mM Tris, 10 mM MgCl₂, 1 mM EDTA, 3 U/mL adenosine deaminase, pH 8.0), in the presence of 0.5 nM [¹²⁵]AB-MECA (p-amino-benzyl-methylcarboxamido-adenosine) (100.000 cpm) and 100 μM R—PIA (N⁶-[L-2-phenylisopropyl]adenosine) to define non-specific binding or test compound in a total volume of 50 μL for 1 hr at room temperature. Filter over Whatman GF/B glass fibre filters (presoaked in 0.5% polyethylenimine for 3 hours), wash 4× with 1 mL ice-cold 50 mM Tris, 10 mM MgCl₂, 1 mM EDTA (pH 8.0) on 96-well Brandel Cell Harvester. Detection of activity: in gamma-counter (1470 Wizard, Wallac). Inhibition [%]=100−((activity in the presence of test compound−non-specific activity)/(total activity−non-specific activity))*100

Human Adenosine A₁ Receptor Binding

Preparing membrane suspension: collect CHO cells expressing hA₁ receptors by washing three times with ice cold PBS, centrifugate at 1000×g 10 min, homogenize for 15 sec in buffer (50 mM Tris, pH 7.4), centrifugate at 43.000×g for 10 min (Sigma 3K30), suspense the membrane preparation in the buffer mentioned above, store the aliquots at −80° C. Binding protocol: incubate CHO—hA₁ membrane preparation (50 μg protein content) in incubation buffer (50 mM Tris, 3 U/mL adenosine deaminase, pH 7.4), 10 nM [³H]CCPA (2-chloro-N⁶-cyclopenthyl-adenosine) (80,000 dpm) and 10 μM R-PIA (N⁶-[L-2-phenylisopropyl]adenosine) to define the non-specific binding or test compound in a total volume of 100 μL for 3 hr at room temperature. Filter over Whatman GF/B glass fibre filters (presoaked in 0.5% polyethylenimine for 3 hours), wash 4× with 1 mL ice-cold 50 mM Tris (pH 7.4) on 96-well Brandel Cell Harvester. Detection of activity: in 96-well plate in the presence of HiSafe-3 cocktail in beta-counter (1450 Microbeta, Wallac). Inhibition [%]=100−((activity in the presence of test compound−non-specific activity)/(total activity−non-specific activity))*100

Human Adenosine A_(2a) Receptor Binding

Binding protocol: incubate 7 μg of membranes (human A_(2a) adenosine receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.), buffer (50 mM Tris-HCl, 10 mM MgCl₂, 1 mM EDTA, 2 U/mL adenosine deaminase, pH 7.4), 20 nM [³H]CGS-21680 (2-[p-(2-carbonylethyl)phenylethylamino]-5′-N-ethylcarboxamido-adenosine) (200.000 dpm) and 50 μM NECA (5′-N-ethylcarboxamido-adenosine) to define the non-specific binding or test compound in a total volume of 100 μl for 90 min at room temperature. Filter over Whatman GF/B glass fibre filters (presoaked in 0.5% polyethylenimine), wash 4× with 1 mL ice-cold 50 mM Tris, 10 mM MgCl₂, 1 mM EDTA, 0.9% NaCl, pH 7.4) on 96-well Brandel Cell Harvester. Detection of activity: in 96-well plate in the presence of HiSafe-3 cocktail in beta-counter (1450 Microbeta, Wallac). Inhibition [%]=100−((activity in the presence of test compound−non-specific activity)/(total activity−non-specific activity))*100

Human Adenosine A_(2b) Receptor Binding

Binding protocol: incubate 20.8 μg of membranes (human A_(2b) adenosine receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.), buffer (50 mM Tris-HCl, 10 mM MgCl₂, 1 mM EDTA, 0.1 mM benzamidine, 2 U/mL adenosine deaminase, pH 6.5), 32.4 nM [³H]DPCPX (8-cyclopenthyl-1,3-dipropylxanthine) (800.000 dpm) and 100 μM NECA (5′-N-ethylcarboxamido-adenosine) to define non-specific binding or test compound in a total volume of 100 μL for 30 min at room temperature. Filter over Whatman GF/C glass fibre filters (presoaked in 0.5% polyethylenimine), wash 4× with 1 mL ice-50 mM Tris-HCl (pH 6.5) on 96-well Brandel Cell Harvester. Detection of activity: in 96-well plate in the presence of HiSafe-3 cocktail in beta-counter (1450 Microbeta, Wallac). Inhibition [%]=100−((activity in the presence of test compound−non-specific activity)/(total activity−non-specific activity))*100

Results

We consider the compounds as biologically active ones if they inhibit the binding of the radioligand on human adenosine A₃ receptors with an activity above 80 % at 1 μM in our experimental conditions.

The dissociation constant (K_(d)) of [¹²⁵I]AB-MECA on CHO-hA₃ membrane preparation is determined by isotope saturation studies with the help of Scatchard analysis (G. Scatchard, Ann. N.Y. Acad. Sci. 51:660, 1949). The IC₅₀ is converted to an affinity constant (K_(i)) by application of the Cheng-Prusoff equation (Y. J. Cheng and W. H. Prusoff, Biochem. Pharmacol. 22:3099, 1973).

Several compounds of the general formula (I), (II), (III) and (IV) display remarkable biological effects. The compounds of the general formula (IA), defined in claim 2, as a subgroup of the general formula (I), defined in claim 1, exert the most important activities. Except of 5 compounds, their K_(i) values are not higher than 20 nM. The compounds given as examples are especially advantageous. Their K_(i) values in human adenosine A₃ receptor binding studies are between 0.19 and 0.69 nM. The K_(i) values of the most advantageous compounds are 0.14 and 0.15 nM.

The compounds possess proper bioviabilities and exert at least 10,000-fold selectivity in respect of human adenosine A₁, A_(2a) and A_(2b) receptor subtypes.

Further, the duration of their action at intravenous and oral administration is long enough, their ED₅₀ values are low, their toxicological and side-effect profiles are advantageous.

Data above make the compounds of the general formula (I) probable for therapeutic applications. 

1. Compounds of the general formula (I)

wherein R¹ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl group; R² stands for hydrogen atom or a straight or branched C₁₋₄ alkyl group; R³ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl group, or a phenyl group, thienyl group, or furyl group, optionally substituted by one or more straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, or halogen atom, or for one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom containing 5- or 6 membered heteroaromatic ring, optionally substituted by one or more straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, or halogen atom; R⁴ and R⁵ stand for hydrogen atom or form together an 1,3-butadienyl group, optionally substituted by a methylenedioxy group or one or more straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, hydroxy group or halogen atom; R⁶ stands for hydrogen atom or a cyano group, aminocarbonyl group, C₁₋₄ alkoxycarbonyl group, or carboxy group; R⁷ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl group, a phenyl group, benzyl group, thienyl group or furyl group, optionally substituted by a methylenedioxy group, or one or more straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom, or for one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom containing 5 or 6 membered heteroaromatic ring, optionally substituted by one or more straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, or halogen atom; X stands for a —CH₂— group, —NH— group, —NR⁸— group, or a sulphur atom or an oxygen atom or a sulpho group or a sulphoxy group— wherein R⁸ stands for a straight or branched C₁₋₄ alkyl group or C₃₋₆ cycloalkyl group—; n stands for zero, 1 or 2— and their salts and solvates, optically active isomers and their salts and solvates.
 2. Compounds of the general formula (IA)

according to claim 1—wherein R¹ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl group; R² stands for hydrogen atom or a straight or branched C₁₋₄ alkyl group; R³ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl group, or a phenyl group, thienyl group, or furyl group, optionally substituted by one or more straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, or halogen atom, or for one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom containing 5- or 6 membered heteroaromatic ring, optionally substituted by one or more straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, or halogen atom; R⁹, R¹⁰, R¹¹ or R¹² stand independently from each other for hydrogen atom, or straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, hydroxy group or halogen atom; or R⁹ and R¹² stand for hydrogen atom and R¹⁰ and R¹¹ form together a methylendioxy group; R⁶ stands for hydrogen atom or a cyano group, aminocarbonyl group, C₁₋₄ alkoxycarbonyl group, or carboxy group; R⁷ stands for hydrogen atom or a straight or branched C₁₋₄ alkyl group, a phenyl group, benzyl group, thienyl group or furyl group, optionally substituted with a methylenedioxy group, or one or more straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom, or for one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom containing 5 or 6 membered heteroaromatic ring, optionally substituted with one or more straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, or halogen atom; X stands for a —CH₂— group, —NH— group, —NR⁸— group, or a sulphur atom or an oxygen atom or a sulpho group or a sulphoxy group—wherein R⁸ stands for a straight or branched C₁₋₄ alkyl group or C₃₋₆ cycloalkyl group—; n stands for zero, 1 or 2— and their salts and solvates, optically active isomers and their salts and solvates.
 3. Compounds of the formula (IA) according to claim 2, —wherein R¹ stands for hydrogen atom or a methyl group; R² stands for hydrogen atom or a methyl group; R³ stands for phenyl group, thienyl group or furyl group; R⁹, R¹⁰, R¹¹ or R¹² stand independently from each other for hydrogen atom, or straight or branched C₁₋₄ alkyl group, straight or branched C₁₋₄ alkoxy group, hydroxy group or halogen atom; or R⁹ and R¹² stand for hydrogen atom and R¹⁰ and R¹¹ form together a methylendioxy group; R⁶ stands for hydrogen atom or cyano group; R⁷ stands for 4-methoxyphenyl group, 3-methylphenyl group, 3-thienyl group or 3-furyl group; X stands for —NH— group or oxygen atom and n stands for 1— and their salts, solvates and optically active isomers and their salts and solvates.
 4. Compounds according to claim 1 chosen from: 3-Methyl-N-(4-benzylamino-3-cyano-quinolin-2-yl)benzamide; 4-Methoxy-N-(4-benzylamino-3-cyano-quinolin-2-yl)benzamide; 3-Methoxy-N-(4-benzylamino-3-cyano-quinolin-2-yl)benzamide; 3,4-Methylenedioxy-N-(4-benzylamino-3-cyano-quinolin-2-yl)benzamide; N-(4-benzylamino-3-cyano-quinolin-2-yl)thiophene-3-carboxamide; N-(4-[2-thienylmethylamino]-3-cyano-quinolin-2-yl)thiophene-3-carboxamide; 4-Methoxy-N-(4-[2-thienylmethylamino]-3-cyano-quinolin-2-yl)benzamide; 3,4-Methylenedioxy-N-(4-[2-thienylmethylamino]-3-cyano-quinolin-2-yl)benzamide; N-(4-[2-furylmethylamino]-3-cyano-quinolin-2-yl)furan-2-carboxamide; N-(4-[2-furylmethylamino]-3-cyano-quinolin-2-yl)thiophene-2-carboxamide; and their salts, solvates, optically active isomers and their salts and solvates.
 5. Process for the preparation of a compound of the general formula (I), its salts, solvates, optically active isomers and their salts and solvates—wherein in the formula R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X and n have the same meaning as defined in claim 1, characterized by selective hydrolysis of a bis acid amide of the general formula (II)

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X and n have the same meaning as defined in claim 1— and if desired transforming the substituents of the compound of the general formula (I) thus obtained in each other by methods known per se and/or transforming the compound of the general formula (I) thus obtained into its salts, or solvates, or liberating it from its salts or solvates and/or separating it into its optically active isomeric forms or transforming the optically active forms into the racemic form.
 6. Process according to claim 5, characterized by carrying out the selective hydrolysis in an alcoholic medium in the presence of an alkali hydroxide.
 7. Pharmaceutical compositions containing as active ingredient one or more compounds of the general formula (I) according to claim 1 or their salts, solvates, or optically active isomers and the salts, solvates thereof, in admixture with one or more excipients used in the pharmaceutical industry.
 8. Pharmaceutical compositions containing as active ingredient one or more compounds of the general formula (IA) according to claim 2 or their salts, solvates, or optically active isomers and the salts, solvates thereof, in admixture with one or more excipients used in the pharmaceutical industry.
 9. Pharmaceutical composition containing as active ingredient one or more compounds of claim 4 or their salts, solvates, or optically active isomers and the salts or solvates thereof in admixture with one or more excipients used in the pharmaceutical industry.
 10. A method for the treatment of asthma, COPD and ARDS, glaucoma, allergic and inflammatory diseases, ischemia, hypoxia, arrhythmia and renal diseases, which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim
 1. 11. A method for the treatment of asthma, COPD and ARDS, glaucoma, allergic reactions, inflammatory diseases, ischemia, hypoxia, arrhythmia, and renal diseases, which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim
 2. 12. Compounds of the general formula (II)

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X and n have the same meaning as defined in claim
 1. 13. Compounds of the general formula (III)

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, X and n have the same meaning as defined in claim 1, with the proviso that R³ cannot stand for phenyl group, if R¹ and R² stand for hydrogen atom, n=1, X stands for a —NH— group, R⁴ and R⁵ form together an 1,3-butadienyl group and R⁶ stands for a cyano group, with the further proviso that R³ cannot stand for a hydrogen atom, straight or branched C₁₋₄ alkyl group, or a phenyl group, substituted by a straight or branched C₁₋₄ alkoxy group, if, n=0, X stands —NH— or —NR⁸, wherein R⁸ is as defined in claim 1, R⁴ and R⁵ form together a 1,3-butadienyl group and R⁶ stands for a cyano group, and with the further proviso that R³ cannot stand for hydrogen atom if—, n=0, X stands for a —CH₂— group, R⁴ and R⁵ form together a 1,3-butadienyl group and R⁶ stands for a cyano or amino-carbonyl group.
 14. Compounds of the general formula (IV)

wherein R⁴, R⁵, and R⁶ have the same meaning as defined in claim 1, with the proviso that R⁶ cannot stand for hydrogen atom, if R⁴ stands for hydrogen atom and R⁵ stands for a hydrogen atom.
 15. Pharmaceutical compositions containing as active ingredient one or more compounds of the general formula (I) according to claim 3 or their salts, solvates, or optically active isomers and the salts, solvates thereof, in admixture with one or more excipients used in the pharmaceutical industry.
 16. Process according to claim 6 wherein the alkali hydroxide is potassium or sodium hydroxide.
 17. A method for the treatment of asthma, COPD and ARDS, glaucoma, allergic reactions, inflammatory diseases, ischemia, hypoxia, arrhythmia, and renal diseases, which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim
 3. 18. A method for the treatment of asthma, COPD and ARDS, glaucoma, allergic reactions, inflammatory diseases, ischemia, hypoxia, arrhythmia, and renal diseases, which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim
 4. 